Structures of SARS-CoV-2 B.1.351 neutralizing antibodies provide insights into cocktail design against concerning variants

Du, Shuo; Liu, Pulan; Zhang, Zhiying; Xiao, Tianhe; Yasimayi, Ayijiang; Huang, Weijin; Wang, Youchun; Cao, Yunlong; Xie, X. Sunney; Xiao, Junyu

doi:10.1101/2021.07.30.454402

Cited by 3 publications

(3 citation statements)

References 10 publications

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“…These mAbs were chosen because they had appreciable activity against the initial Omicron variant. Among these antibodies, 20 were directed to the class 1 to class 4 epitope clusters on the RBD (Barnes et al, 2020): S2K146 (Park et al, 2022), Omi-3 (Nutalai et al, 2022), Omi-18 (Nutalai et al, 2022), BD-515 (Cao et al, 2021), XGv051 (Wang et al, 2022b), XGv347 (Wang et al, 2022a), ZCB11 (Zhou et al, 2022), COV2-2196 (tixagevimab) (Zost et al, 2020), LY-CoV1404 (bebtelovimab, authorized to treat COVID-19) (Westendorf et al, 2022), XGv289 (Wang et al, 2022a), XGv264 (Wang et al, 2022b), S309 (sotrovimab) (Pinto et al, 2020), P2G3 (Fenwick et al, 2022), SP1-77 (Luo et al, 2022), BD55-5840 (Cao et al, 2022), XGv282 (Wang et al, 2022a), BD-804 (Du et al, 2021), 35B5 (Wang et al, 2022g), COV2-2130 (cilgavimab) (Zost et al, 2020), and 10-40 (Liu et al, 2022a). The other three were non-RBD mAbs, with C1520 (Wang et al, 2022h) targeting the NTD, C1717 (Wang et al, 2022h) targeting NTD-SD2, and S3H3 (Hong et al, 2022) targeting SD1.…”

Section: Resultsmentioning

confidence: 99%

Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants

Wang

Iketani

et al. 2022

Preprint

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The SARS-CoV-2 Omicron variant continues to evolve, with new BQ and XBB subvariants now rapidly expanding in Europe/US and Asia, respectively. As these new subvariants have additional spike mutations, they may possess altered antibody evasion properties. Here, we report that neutralization of BQ.1, BQ.1.1, XBB, and XBB.1 by sera from vaccinees and infected persons was markedly impaired, including sera from individuals who were boosted with a WA1/BA.5 bivalent mRNA vaccine. Compared to the ancestral strain D614G, serum neutralizing titers against BQ and XBB subvariants were lower by 13-81-fold and 66-155-fold, respectively, far beyond what had been observed to date. A panel of monoclonal antibodies capable of neutralizing the original Omicron variant, including those with Emergency Use Authorization, were largely inactive against these new subvariants. The spike mutations that conferred antibody resistance were individually studied and structurally explained. Finally, the ACE2-binding affinities of the spike proteins of these novel subvariants were found to be similar to those of their predecessors. Taken together, our findings indicate that BQ and XBB subvariants present serious threats to the efficacy of current COVID-19 vaccines, render inactive all authorized monoclonal antibodies, and may have gained dominance in the population because of their advantage in evading antibodies.

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Section: Resultsmentioning

confidence: 99%

Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants

Wang

Iketani

et al. 2022

Preprint

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“…A large number of additional antibodies are also in competition for bids with ACE2. Before the emergence of the omicron variant, previous studies showed that a large number of antibodies were still effectively neutralizing SARS-CoV-2 variants [31]. However, recent findings indicate that 85% of previously described neutralizing antibodies are no longer effective against the novel omicron Variant [32].…”

Section: Rbd-ace2 Protein Dockinmentioning

confidence: 99%

Molecular and computational analysis of spike protein of newly emerged omicron variant in comparison to the delta variant of SARS-CoV-2 in Iraq

Rashid

Salih

2022

Mol Biol Rep

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Background The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) has had a major impact on world health over the last 2 years. The emergence of SARS-CoV-2 variants, particularly concerning variants, may affect the virus's pathogenicity, transmissibility, and vaccines potency. Both delta and the omicron variants have been designated by WHO as variants of concern. Methods and resultsIn this study, molecular techniques such as qPCR, conventional PCR, and sequencing were used to identify the first SARS-CoV-2 omicron variant that circulated in Iraq in January 2022. Bioinformatics and computational tools like phylogenetic analysis, predicted physical and chemical properties, stability, and molecular docking of the spike protein were used to compare the omicron with the delta variants. We found the receptor binding domain (RBD) and spike protein in omicron contain a greater number of hydrophobic amino acids compared to delta variant. We discovered a disorder-order conversion in RBD regions of the omicron variant, and this change may be important in terms of the effect of disordered residues/regions on spike protein stability and interaction with human angiotensin converting enzyme 2 (ACE2). Docking studies show that the omicron variant requires less energy to engage with ACE2, contributing to its higher binding affinity with human ACE2, consistent with more contagious transmission. Conclusion This is the first molecular study of the circulated omicron and delta variants in Iraq, showing that the omicron variant in Iraq had a higher affinity for ACE2 than the delta variant, which may lead to higher transmissibility.

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“…Samples for cryo-EM study were prepared essentially as described 15,52 (Supplementary Table 4). All EM grids were evacuated for 2 min and glow-discharged for 30 s using a plasma cleaner (Harrick PDC-32G-2).…”

Section: Cryo-em Data Collection Processing and Structure Buildingmentioning

confidence: 99%

BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron BA.1 infection

Xie¹,

Cao

Yisimayi

et al. 2022

Preprint

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Recent emergence of SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.2.13, BA.4 and BA.5 all contain L452 mutations and show potential higher transmissibility over BA.2. The new variants’ receptor binding and immune evasion capability require immediate investigation, especially on the role of L452 substitutions. Herein, coupled with structural comparisons, we showed that BA.2 sublineages, including BA.2.12.1 and BA.2.13, exhibit increased ACE2-binding affinities compared to BA.1; while BA.4/BA.5 shows the weakest receptor-binding activity due to F486V and R493Q reversion. Importantly, compared to BA.2, BA.2.12.1 and BA.4/BA.5 exhibit stronger neutralization escape from the plasma of 3-dose vaccinees and, most strikingly, from vaccinated BA.1 convalescents. To delineate the underlying evasion mechanism, we determined the escaping mutation profiles, epitope distribution and Omicron sub-lineage neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype-induced humoral memory and elicits antibodies that neutralize both wild-type and BA.1. These cross-reactive NAbs are significantly enriched on non-ACE2-competing epitopes; and surprisingly, the majority are undermined by R346 and L452 substitutions, namely R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5), suggesting that R346K and L452 mutations appeared under the immune pressure of Omicron convalescents. Nevertheless, BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1 but do not respond to wild-type SARS-CoV-2, due to the high susceptibility to N501, N440, K417 and E484. However, these NAbs are largely escaped by BA.2 sublineages and BA.4/BA.5 due to D405N and F486V, exhibiting poor neutralization breadths. As for therapeutic NAbs, LY-CoV1404 (Bamlanivimab) and COV2-2130 (Cilgavimab) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum protection.

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Structures of SARS-CoV-2 B.1.351 neutralizing antibodies provide insights into cocktail design against concerning variants

Cited by 3 publications

References 10 publications

Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants

Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants

Molecular and computational analysis of spike protein of newly emerged omicron variant in comparison to the delta variant of SARS-CoV-2 in Iraq

BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron BA.1 infection

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